Pharmacology & toxicology
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Pharmacology & toxicology · Oct 2003
Comparative StudyPhenylephrine induces endogenous noradrenaline release in the rat vas deferens through nitric oxide synthase pathway.
We have previously observed that in the rat vas deferens nitric oxide synthase pathway potentiated phenylephrine-induced contractility raising the possibility of a facilitatory role on neurotransmission by nitric oxide. To confirm this hypothesis we studied the effect of phenylephrine on the concentration response curves obtained in preparations from reserpine-treated rats in the absence and presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). The endogenous noradrenaline released by normal preparations (without reserpine) was measured in the perfusion fluid of preparations stimulated with phenylephrine, in the absence and presence of L-NMMA, L-NMMA + the nitric oxide donor 3-morpholinosydnonimine hydrochloride (SIN-1), the alpha1-adrenoceptor antagonist prazosin and the blocker of noradrenaline carrier desipramine. ⋯ The concentration-dependent phenylephrine-induced noradrenaline increase was not modified by desipramine but was abolished by 10 microM prazosin. In calcium-free medium, phenylephrine failed to increase the noradrenaline concentration. These results suggest that in the rat vas deferens, nitric oxide pathway potentiates the phenylephrine-induced contractility through a mechanism which involves calcium-dependent release of endogenous noradrenaline and seems to depend, at least partially on the activation of alpha1-adrenoceptors.
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Pharmacology & toxicology · Jun 2003
Comparative Study Clinical Trial Controlled Clinical TrialComparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers.
To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. ⋯ The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.
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Pharmacology & toxicology · Aug 2001
ReviewAspects on the pathophysiology of migraine and cluster headache.
The specific cause of migraine headache remains unknown. Current theories suggest that the initiation of a migraine attack involves a primary CNS dysfunction with subsequent activation of the trigeminovascular system. ⋯ Triptan administration, activating the 5-HT(1B/1D) receptors, caused the headache to subside and the neuropeptide release to normalise. These data suggest the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headaches.
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Pharmacology & toxicology · Aug 2001
GABA mechanisms and antinociception in mice with ligated sciatic nerve.
In the present study, the effects of GABA (gamma-aminobutyric acid) receptor agonists and antagonists on hyperalgesia induced by sciatic nerve ligation was investigated in mice. The response to morphine or GABA receptor agonists was examined 14 days after unilateral nerve ligation by hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), muscimol (0.5, 1 and 2 mg/kg) or baclofen (1, 2.5 and 5 mg/kg) induced a dose-related antinociception in both intact and ligated mice. ⋯ However, morphine in combination with muscimol (2 mg/kg) tends to induce higher response; the combination of the GABA receptor agonists with morphine did not show potentiation, but additive effect. The opioid receptor antagonist naloxone reduced the response induced by muscimol in nerve-ligated animals. It was concluded that although ligation of the sciatic nerve clearly reduced the analgesic effect of morphine and not that of the GABA agonists, the results nevertheless indicated that morphine and the GABA(A) agonist shared the same mechanism of action.